Glaucoma is one of the two most common forms of blindness, causing millions of cases worldwide. Elevated intraocular pressure (IOP) is the main risk factor and most glaucoma drugs are directed at lowering ocular pressure. While multiple classes of these drugs are available each has limitations and not all patients respond to them. Moreover because glaucoma treatments are required for years or even decades many patients develop tolerance and are left without treatment options. In this context it is important to note that cannabinoids have been found to be effective in patients resistant to standard therapies. 1971 marked the publication of the first work by Hepler & Frank demonstrating that the chief psychoactive ingredient of marijuana - THC - has a salutary effect on intraocular pressure (IOP). This set in motion a 40-year series of studies to learn the nature of this effect, studies that continue today. Because the physiological target was unknown, initial work focused on THC and related phytocannabinoids. With the identification of the cannabinoid CB1 and CB2 receptors and endocannabinoids, 2-AG and anandamide, these receptors and ligands became the target of most subsequent studies. The current proposal represents the next logical extension of these inquiries: 1) to determine the architecture of the ocular endocannabinoid system -- the enzymes that metabolize the endogenous cannabinoids (eCBs) and the enzymes that produce them. Preliminary results show that most 'players' in the cannabinoid signaling system are present in the anterior eye. 2) We propose to enhance endogenous signaling to reduce IOP. We have evidence that blocking MAGL the enzyme most implicated in metabolizing 2-AG lowers IOP and intriguingly that the COX blocker acetaminophen lowers IOP via CB1. Importantly since cannabinoids are strongly implicated in neuroprotection we intend to 3) harness endocannabinoids to protect neurons using several models of ocular pathology. This is important because elevated IOP is not the only risk factor for glaucoma and raises the possibility that cannabinoids may be engaged not only to reduce IOP but also to protect neurons from damage associated with glaucoma. We know surprisingly little about ocular cannabinoids beyond CB1 expression despite the proven potential of cannabinoids to lower IOP and to serve as neuroprotective agents. Glaucoma remains a devastating disease that affects millions; the proposed research has the potential to greatly expand our knowledge of ocular cannabinoid signaling and to identify novel classes of drugs related to ocular health.